The mating process in Saccharomyces cerevisiae is controlled by two G protein-coupled receptors. The receptors, which are expressed specifically in haploid cells of opposite mating types, respond to short, peptide pheromones, alpha-factor and a-factor. We are studying the non-specific interactions of these amphiphilic peptides with yeast plasma membranes and with phospholipid vesicles, and the subsequent interactions of the peptides with the receptors. The pheromones have been chemically synthesized and have been labelled with fluorescent probes to allow the binding events to be monitored spectroscopically. The a-factor peptide contains a C-terminal farnesyl modification, and various alkyl derivatives at this position have been synthesized to study effects on membrane binding and on biological activity. For each of the pheromones, an initial, non-specific interaction with the plasma membrane is thought to be necessary for the subsequent binding to the receptors. The non-specific interactions can be modulated by experimental conditions (e.g., salt concentration, membrane composition, peptide structure) and effects of the conditions on the non-specific binding can be correlated with effects of the conditions on the biological activity of the pheromones. We expect that the results obtained with this simple model system can be applied to other amphiphilic peptide hormones that activate G protein-coupled receptors in higher cells. The services of the UCSF Mass Spectrometry Facility have been crucial in confirming the structures of all of our synthetic peptides.